System and method for non-invasive monitoring of advanced glycation end-products (age)

ABSTRACT

A method of non-invasively monitoring advanced glycation end-product (AGE) concentrations includes providing incident light to patient tissue at one or more excitation wavelengths and monitoring the one or more emission responses at one or more emission wavelengths. Based on the emission responses monitored, a ratio is calculated based on a ratio of the first emission response to the second emission response.

This application is a divisional of U.S. patent application Ser. No.15/866,160, filed Jan. 9, 2018, which issued as U.S. Pat. No. 11,051,727on Jul. 6, 2021. The entire content of U.S. patent application Ser. No.15/866,160 is incorporated herein by reference.

TECHNICAL FIELD

This invention relates generally to patient diagnosis and monitoring,and in particular non-invasive diagnosis and monitoring of advancedglycation end-products (AGE).

BACKGROUND

Advanced glycation end products (AGEs) are proteins or lipids thatbecome glycated as a result of exposure to sugars. AGE is a factor inaging and in the development or worsening of many degenerative diseases,such as diabetes, atherosclerosis, chronic kidney disease, andAlzheimer's disease. AGE formation results from non-enzymatic reactionsbetween sugars and proteins called the Maillard reaction. In the firststep of this reaction, a sugar adduct (e.g., glucose) reacts with aprotein amino group (e.g., NH₂). The Schiff-base then converts into amore stable Amadori product (e.g., glycated hemoglobin or HbA1c). Thisreaction may occur in vivo throughout the body, including the skin,neural, vascular, renal, cardiac tissue, as well as in the patient'sblood (e.g., HbA1c). In patients with diabetes, accelerated AGEaccumulation occurs mainly as a consequence of high glucose levels.Renal failure also contributes to enhanced AGE accumulation.

With respect to hemoglobin (Hb), when the body processes sugar, glucosein the bloodstream naturally attaches to hemoglobin, wherein the amountof glucose that combines with hemoglobin is directly proportional to thetotal amount of sugar in the patient at a given time. The amount ofglycated hemoglobin (referred to herein as “HbA1c”) is therefore areflection of the amount of blood glucoses in a patient over the lastseveral weeks. Monitoring of HbA1c is particularly important forpatients with diabetes or pre-diabetes, and is an indicator as towhether the patient's diabetes is under control.

Similarly, AGE accumulation within the patient's heart can result inexcessive cross-linking of myocardial tissue, which increases therigidity of the tissue and may induce diastolic dysfunction in theheart. In addition, AGE accumulation has been linked to delays incalcium uptake resulting in longer re-polarisation times associated withthe heart, and to the progression of coronary artery disease bynegatively influencing LDL-metabolism.

Typically, monitoring AGE accumulation in patient tissue and/or bloodrequires taking a tissue sample from the patient or blood sample, andthen analyzing the sample in a laboratory. This requires a patient tophysically visit a healthcare center to provide the tissue/blood sample.

It would therefore be advantageous to develop a device that is capableof non-invasive monitoring of AGE accumulations, both in tissue and inblood.

SUMMARY

According to one embodiment, a method of non-invasively monitoringadvanced glycation end-products (AGEs) concentration, the methodincludes providing incident light to patient tissue at a firstexcitation wavelength and monitoring a first emission response to thelight provided at the first excitation wavelength. The method furtherincludes providing incident light to patient tissue at a secondexcitation wavelength and monitoring a second emission response to thelight provided at the second excitation wavelength. The AGEconcentration is calculated based on a ratio of the first emissionresponse to the second emission response.

According to another embodiment, a system for non-invasively monitoringof advanced glycation end-product (AGE) includes a medical device and aprocessing module. The medical device includes a first light emitterconfigured to provide a first excitation signal to patient tissue at afirst wavelength, a second light emitter configured to provide a secondexcitation signal to patient tissue at a second wavelength, and at leastone photodetector configured to monitor an emission response at a firstemission wavelength, wherein the first emission wavelength is selectedto correspond with a maximum of the emission response to either thefirst excitation signal or the second excitation signal. The processingmodule is configured to receive emission responses measured at the firstemission wavelength in response to the first and the second excitationwavelengths, wherein the processing module calculates a ratio based onthe received emission responses and utilizes the calculated ratio todetermine the AGE concentration level.

A method of non-invasively monitoring advanced glycation end-products(AGEs) concentration, the method includes providing incident light topatient tissue at a first excitation wavelength. The first emissionresponse is measured at a first emission wavelength and at a secondemission wavelength. The AGE concentration is calculated based on aratio of the first emission response to the second emission response.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a schematic view of a patient and a patientmonitoring system, according to some embodiments.

FIGS. 2A-2C are perspective views of an adherent monitoring deviceaccording to some embodiments.

FIG. 3 is a perspective view of an insertable monitoring deviceaccording to some embodiments.

FIG. 4 is a block diagram illustrating components utilized to monitoroptical signals and processing optical signals according to someembodiments.

FIG. 5 is a flowchart that illustrates steps utilized to measureadvanced glycation end-products (AGE) according to an embodiment of thepresent invention.

FIG. 6 is a graph that illustrates relative absorbance of HbA1c atvarious wavelengths.

FIG. 7 is a graph that illustrates the relationship between emissionresponse intensity and HbA1c concentration.

FIG. 8 is flowchart that illustrates steps utilized to measure advancedglycation end-products (AGE) according to another embodiment of thepresent invention.

FIG. 9 is a graph that illustrates the excitation spectrum and emissionspectrum for HbA1c concentrations.

FIG. 10 is flowchart that illustrates steps utilized to measure advancedglycation end-products (AGE) utilizing fluorescent decay according toanother embodiment of the present invention.

FIG. 11 is a graph that illustrates the autofluorescent decay for HbA1c.

FIG. 12 is a flowchart that illustrates a method of long-term monitoringof HbA1c concentrations according to an embodiment of the presentinvention.

DETAILED DESCRIPTION

Advanced glycation end products (AGEs) refer generally to proteins orlipids that become glycated as a result of exposure to sugars. Thepresent invention can be utilized to non-invasively monitor varioustypes of AGEs occurring in patient tissue. Depending on the particularAGE protein or lipid to be monitored, one or more excitation wavelengthsare selected and one or more emission wavelengths are monitored. Forexample, patient tissue/blood may be exposed to two or more excitationwavelengths selected to generate a significant emission response (e.g.,maximum and/or minimum associated with the particular AGE to bemonitored), with first and second emission responses measured at one ormore wavelengths. The ratio of the first and second emission responsesare utilized to calculate the concentration of the particular AGEprotein or lipid to be monitored. In another embodiment, patienttissue/blood may be exposed to a single excitation wavelength, with theemission response measured at first and second wavelengths, wherein thefirst and second wavelengths are selected to correspond with asignificant emission response (e.g., autofluorescence, absorption, andreflectance maximums and/or minimums). The ratio of the emissionresponse at first and second wavelengths is utilized once again tocalculate the concentration of the particular AGE protein or lipid to bemonitored. In another embodiment, patient tissue/blood may be exposed toat least one excitation wavelength selected to generate an emissionresponse. The emission response is measured at one or more wavelengthsover a period of time to generate first and second temporal emissionresponses. A ratio of the first and second temporal emission responsesis utilized to calculate the concentration of the particular AGE proteinor lipid to be monitored.

In particular, an example AGE species is glycated hemoglobin (HbA1c),which is utilized as an indicator for monitoring diabetes risk inpatients. Typically, HbA1c testing requires drawing blood from thepatient and providing the blood to a lab for analysis. The presentdisclosure provides a system and method for non-invasive monitoring ofHbA1c utilizing optical measurements. In one embodiment, a first lightsource emits light at a first excitation wavelength and monitors theemission response. A second light source emits light at a secondexcitation wavelength and the emission response is again measured. Thefirst and second excitation wavelengths are selected to provide emissionresponses related to hemoglobin and HbA1c, respectively. Based on aratio of the amplitudes measured in response to the first and secondexcitation wavelengths, the concentration of HbA1c relative tohemoglobin concentration is determined.

Benefits of this system include the non-invasive nature of monitoring,and real-time feedback provided by using optical means of sensing AGEconcentration levels. Although these levels change very slowly over time(e.g., 30-60 days), and thus do not require continuous monitoring,trends can be developed by monitoring AGE levels at a shorter durationthan once every 30-60 days. In one embodiment, a daily measurement ofAGE concentration levels can detect increasing levels of an AGE proteinor lipid before it reaches problematic levels. For example, the risk ofdiabetes increases with increasing HbA1c levels, resulting in HbA1cconcentrations being particularly useful for detecting pre-diabetes inpatients. In addition, because the test can be done non-invasively andremote from a medical center/office, there is a greater probability ofpatient compliance.

FIG. 1 illustrates a patient P and a monitoring system 10 fornon-invasive monitoring of AGE concentration levels (e.g., glycatedhemoglobin (HbA1c)). In the embodiment shown in FIG. 1, monitoringsystem 10 comprises a patient medical device 100 and/or 110, gateway102, and remote monitoring center 106. In the embodiment shown in FIG.1, patient medical device 100 is an adherent device that attaches to theskin of the patient, and patient medical device 110 is a clip that fitsover a patient's finger. In other embodiments, patient medical devicemay include implantable devices, insertable devices, injectable devices,arm cuff (similar to a blood pressure cuff) and/or wearable devices suchas a Holter monitor (collectively referred to as a medical device). Ineach example, the patient medical device utilizes optical components tomonitor AGE concentration levels (e.g., HbA1c levels) of the patient. Insome embodiments, patient medical device 100 and/or 110 includes one ormore additional sensors for monitoring one or more additionalphysiological parameters of the patient, such as activity, orientation,cardiac activity, hydration, etc.

The location of the patient medical device 100/110 may be selected basedon the AGE protein and/or lipid to be monitored. For example, if AGEconcentration levels in myocardial tissue are to be monitored, then thepatient medical device may be adhered to the patient's thorax. Themedical device may be affixed to the skin of the patient,subcutaneously, or implanted adjacent to the tissue to be excited.

In the embodiment shown in FIG. 1, medical device 100 is adhered to thethorax of patient P, which allows for the monitoring of additionalphysiological parameters, such as ECG, hydration, activity, etc. In manyembodiments, the device may adhere to one side of the patient, fromwhich side data can be collected. A benefit of utilizing an adherentdevice, implantable, injectable, and/or wearable device is that it maybe utilized to collect physiological data from the patient while thepatient goes about normal day-to-day activities outside of a hospitalsetting. A medical device clipped to a patient's finger, such as medicaldevice 110, is not worn throughout the day by a patient, but may beuseful in applications such as these due to the relative ease inapplying the clip to a patient's finger in order to take a reading. Thatis, rather than wearing the device for an extended period of time, apatient may periodically clip the device to the patient's finger for afew moments (e.g., seconds) in order to non-invasively measure an AGEconcentration level, and then removed. For applications such as AGEsmonitoring, in which a single measurement a day may be sufficient, amedical device clipped to the patient's finger (or similarly, an armcuff) may be sufficient.

As discussed above, in some embodiments, the medical device may monitora number of physiological parameters associated with patient P,including optical signals utilized to determine AGE concentrationlevels, electrocardiogram (ECG) signals utilized to detect rhythmabnormalities such as tachycardia and/or bradycardia as well as activitylevel data, posture, bio-impedance, blood pressure (associated with ablood pressure cuff), etc. Analysis of one or more of thesephysiological parameters may be done locally by the medical devices 100or 110, or remotely by gateway 102 and/or remote monitoring center 106(or similar platform separate from the local medical device 100).Non-invasive monitoring of AGEs concentration levels relies on one ormore optical sensors positioned on the medical device to provide one ormore excitation sources (e.g., light) to patient tissue and monitor theemission response (e.g., light emitted by the patient tissue as a resultof reflection, fluorescence, absorbance of the incident light). Forexample, in one embodiment one or more light sources associated with themedical device direct incident light to patient tissue. In addition, oneor more photodetectors associated with the medical device receives lightemitted from the patient at a particular emission wavelength associatedwith the photodetector. The photodetector converts the measured emission(i.e., optical signal) to an electrical signal that is representative ofthe amplitude or strength of the emitted light. As discussed in moredetail below, analysis of the detected optical signal can be utilized tomonitor AGE concentration levels such as HbA1c. In some embodiments, theanalysis is performed locally by the medical device 100 or 110, while inother embodiments the monitored optical signal is transmitted to agateway 102 or remote center 106 for analysis to detect concentrationlevels in blood.

In one embodiment, gateway 102 comprises components of the zLink™, asmall portable device similar to a cell phone that wirelessly transmitsinformation received from medical device 100 to remote monitoring center106. The gateway 102 may consist of multiple devices, which cancommunicate wired or wirelessly with remote center 106 in many ways, forexample with a connection 104 which may comprise an Internet connectionand/or with a cellular connection. Remote center 106 may comprise ahosted application for data analysis and storage that also includes awebsite, which enables secure access to physiological trends andclinical event information for interpretation and diagnosis. Remotecenter 106 may further or alternatively comprise a back-end operationwhere physiological data from adherent devices 100 or 110 are read byhuman experts to verify accuracy. Reports may then be generated atremote monitoring center 106 for communication to the patient'sphysician or care provider. As discussed above, in other embodimentsgateway 102 may be implemented with a user device such as a smartphone,tablet, or computer capable of storing and executing one or moreapplications capable of processing data received from medical devices100 and/or 110, as well as communicating the received data to remotemonitoring center 106.

In an exemplary embodiment, the monitoring system comprises adistributed processor system with at least one processing module (notshown) included as part of adherent device 100 and/or 110, at least oneprocessor 102P of gateway 102, and at least one processor 106P at remotecenter 106, each of which processors can be in electronic communicationwith the other processors. At least one processor 102P comprises atangible medium 102T, and at least one processor 106P comprises atangible medium 106T. Remote processor 106P may comprise a backendserver located at the remote center. Physiological parameters—includingoptical signals—monitored by medical device 100 and/or 110 may beanalyzed by one or more of the distributed processors included as partof medical device 100 and/or 110, gateway 102, and/or remote monitoringcenter 106.

FIGS. 2A-2C are perspective views of an adherent monitoring deviceaccording to some embodiments. Adherent devices are adhered to the skinof a patient, and include one or more sensors utilized to monitorphysiological parameters of the patient. Adherent devices areoften-times utilized for long-term monitoring of ambulatory patients,allowing physiological parameters of the patient to be monitored over aperiod of time (e.g., days, weeks, months). Adherent devices thereforeallow for both long-term monitoring of patients with chronic conditions(e.g., diabetes, heart failure) as well as monitoring and detection ofacute incidences (e.g., carbon monoxide poisoning), and can be utilizedto provide dynamic monitoring (e.g., monitoring in response to a triggeror detected condition). This is in contrast with typical blood/tissuetests, which require blood be drawn by a lab and therefore do not allowfor either long-term monitoring or detection of acute conditions.

The adherent device 200 illustrated in FIG. 2A illustrates therelatively low profile of adherent devices, which allows patients towear the devices comfortably over a long period of time.

In the embodiment shown in FIG. 2B, a bottom surface 202 of adherentdevice 200 is shown, which includes a plurality of electrodes 204 a-204d, first and second light emitters 206 a and 206 b, and first and secondphotodetectors 208 a, 208 b. Electrodes 204 a-204 d are utilized tomonitor electrical activity associated with the patient, includingmonitoring electrocardiogram (ECG) information and bio-impedance. Firstand second light emitters 206 a and 206 b are utilized to generateexcitation signals (e.g., incident light) at first and second excitationwavelengths. Depending on the particular AGE protein and/or lipid to bemonitored (e.g., HbA1c), different wavelengths of light may be selectedin order to generate a particular emission response, which refers to howthe incident light at a particular wavelength interacts with the AGEprotein or lipid via reflectance, absorbance, fluorescence, etc., whichis represented by the light emitted from the patient. For example,hemoglobin (Hb) is defined by an emission response to incident lightprovided at a particular wavelength. Similarly, glycated hemoglobin(HbA1c) is defined by an emission response to incident light provided ata different wavelength. In some embodiments, first and second excitationwavelengths are selected to generate significant emission responses forthe particular protein and/or lipid being targeted for monitoring.

In addition, the embodiment shown in FIG. 2B, the bottom surface 202 ofadherent device 200 includes two or more photodetectors 208 a, 208 b. Inthis embodiment, each photodetector is configured to detect light at aparticular emission wavelength. The wavelength selected is based on theemission response of the AGE protein/lipid being monitored (e.g., HbA1c,etc.). In a lab environment, the entire spectral response (e.g., allwavelengths) may be measured and analyzed. This is cost prohibitivethough in an adherent device. Instead of monitoring all wavelengths, theembodiment shown in FIG. 2B selects one or more wavelengths to monitor.The wavelengths are selected based on the particular AGE protein/lipidbeing analyzed, and are selected to correlate with either maximums orsignificant minimums associated with the AGE emission response beingmonitored For example, hemoglobin is defined by an emission responsemorphology that includes a maximum at a wavelength of approximately 575nm, and a minimum at wavelengths greater than 560 nm. In this example,photodetector 208 a may be configured to monitor an attribute (e.g.,amplitude) of the emission response provided at a wavelength of 575 nm,and photodetector 208 b may be configured to monitor an attribute (e.g.,amplitude) of the emission response provided at a wavelength of 560 nm.As discussed below, the ratio of the maximum measurement to minimummeasurement are utilized to determine the concentration of the targetedAGE protein/lipid. In other embodiments, one photodetector 208 a isconfigured to monitor an emission wavelength associated with a maximumassociated with a first protein/lipid (e.g., hemoglobin (Hb) andphotodetector 208 b is configured to monitor an emission wavelengthassociated with a maximum associated with a second protein/lipid(HbA1c). In this embodiment, the ratio of the maximum measurementassociated with a first targeted protein/lipid to the maximummeasurement associated with a second targeted protein/lipid are utilizedto determine the concentration of the targeted AGE protein/lipidsrelative to one another. In another embodiment, photodetectors 208 aand/or 208 b may be utilized to monitor first and second temporalattribute of the emission response (e.g., average amplitude over aperiod of time, rate of change, etc.), wherein a ratio is generatedbased on the first and second temporal attributes to determine theconcentration of the targeted AGE protein/lipid relative to one another.

In this way, emission response ratios can be created by selectivelyapplying first and second excitation wavelengths to generate separatefirst and second emission responses. In other embodiments, the ratio canbe created by selectively applying a single excitation wavelength andwith respect to the emission response, utilizing a first emissionwavelength and second emission wavelength to generate the desired ratio.

Based on the measured attribute of emitted light at select wavelengths,a ratio of the measured attributes is calculated, wherein the ratioprovides a measure of the AGE protein/lipid concentration. A benefit ofutilizing a ratio is that the measure is relatively immune to noise andexternal factors such as change in ambient light intensity, moleculeconcentrations, artifacts, light source instability, detectorinstability, and/or changes in placement of the sensor. For example, ameasurement taken during the night in which little or no external lightis available may provide an amplitude that is much lower than theamplitude measured if the patient is outside in the sun—in which lightfrom the sun increases the measured amplitude at both the minimum andthe maximum.

Although in the embodiment shown in FIG. 2B, a pair of emitters 206 aand 206 b is shown along with a pair of detectors 208 a and 208 b,additional emitters may be utilized along with additional detectors. Inaddition, although each emitter and detector is illustrated as aseparate entity, in some embodiments the functions of an emitter anddetector are included in a single device. Therefore, on one embodimentlight source 206 may also include a photodetector 208. Photodetectorsmay be implemented with well-known imaging sensors such as CCD or CMOSimage sensors.

In the embodiment shown in FIG. 2C, rather than utilize a two or moredetectors, adherent device 210 includes a single photodetector 214. Inthis embodiment, each light source or emitter 212 a and 212 b once againprovides incident light at a unique wavelength selected to generate anemission response related to the AGE protein/lipid to be monitored.Photodetector 214 monitors emissions at a single wavelength, selected tocorrespond with a maximum of the emission response associated with thefirst excitation wavelength or the second excitation wavelength. Forexample, in one embodiment the first excitation wavelength is selectedto provide a significant (e.g. maximized) first emission responseassociated with AGE proteins, and wherein the second excitationwavelength is selected to provide a significant minimum emissionresponse from the same AGE protein/lipid (e.g., HbA1c). Thephotodetector 214 monitors the respective emission responses at awavelength selected to correspond with a maximum of the first emissionresponse and a significant minimum of the second emission response. Inthis embodiment, selective variation of the excitation wavelengthcreates the desired difference/ratio in the emission response.

In some embodiments, emitters 212 a and 212 b are controlled to generateincident light mutually exclusive of one another (e.g., one at a time).This allows detector 214 to measure the emission response associatedwith the first excitation wavelength and the emission responseassociated with the second excitation wavelength, separately. Forexample, in one embodiment emitter 212 a is activated to provideincident light at a first excitation wavelength. Photodetector 214measures an attribute (e.g., amplitude) relating to the emissionresponse at a given emission wavelength. Subsequently, emitter 212 a isdeactivated and emitter 212 b is activated to provide incident light ata second excitation wavelength. Photodetector 214 measures the attribute(e.g., amplitude) relating to the emission response at the same givenemission wavelength. The ratio of the measured amplitudes is utilized tomeasure a blood concentration component and or a blood concentrationcomponent level (e.g., Hg) relative to another blood concentration level(e.g., HbA1c).

In other embodiments, more than two light sources (e.g., emitters) maybe utilized to provide incident light at more than two unique excitationwavelengths. In addition, more than a single photodetector may beutilized in order to measure attributes of the emission response at aplurality of emission wavelengths. Similarly, although a pair ofemitters 212 a and 212 b and a single photodetector 214 are utilized inFIG. 2C, in other embodiments more than two emitters may be utilizedalong with a plurality of photodetectors. In addition, although eachemitter and photodetector is illustrated as a separate entity, in someembodiments the functions of an emitter and photodetector are includedin a single element.

FIG. 3 is a perspective view of an insertable monitoring device 300according to some embodiments. In contrast with an adherent device,which is secured to the skin of a patient, insertable monitoring devices300 are inserted subcutaneously. Insertable device 300 includes at leastfirst and second electrodes 302 a and 302 b, at least one light emitter304 (emitters 304 a and 304 b are shown) and at least one photodetector308 (photodetectors 308 a and 308 b are shown). As discussed above withrespect to FIGS. 2B and 2C, insertable monitoring device 300 utilizesthe at least one emitter to emit light at an excitation wavelengthselected based on the AGE protein/lipid to be monitored (e.g., HbA1c).The at least one photodetector 308 may be utilized to monitor one ormore emission wavelengths, selected to correlate with maximums and/orminimums of the AGE protein/lipid to be monitored (e.g., maximumassociated with Hb and maximum associated with HbA1c). As described withrespect to FIGS. 2A-2C, emission response ratios can be created byselectively applying first and second excitation wavelengths to generateseparate first and second emission responses. In other embodiments, theratio can be created by selectively applying a single excitationwavelength and with respect to the emission response, utilizing a firstemission wavelength and second emission wavelength to generate thedesired ratio.

For example, in one embodiment insertable monitoring device 300 isconfigured to generate light at a first excitation wavelength selectedto generate an emission response having a maximum responsive to an AGEprotein/lipid, and measures the emission response at a wavelength thatcorresponds with a maximum (peak) of the emission response. In addition,monitoring device 300 generates light at a second excitation wavelengthselected to generate an emission response having a maximum responsive toa second protein/lipid (e.g., AGE protein/lipid or non-AGE protein/lipidsuch as hemoglobin (Hb)). An emission response to the second excitationwavelength is measured at a wavelength that corresponds with a maximum(peak) of the emission response (same or different wavelength as thatutilized for monitoring the first AGE protein/lipid). A ratio iscalculated based on a first emission response monitored with respect tothe first excitation wavelength and a second emission response monitoredwith respect to the second excitation wavelength (wherein the first andsecond emission response may be at the same emission wavelength orunique emission wavelengths). For example, in one embodiment the AGEprotein/lipid selected by the first excitation wavelength is glycatedhemoglobin (HbA1c) and the second protein/lipid selected by the secondexcitation wavelength is hemoglobin (Hb), such that the ratio describesthe relationship between concentration of HbA1c and Hb, which is usefulin monitoring the progression of conditions such as pre-diabetes ordiabetes.

In another embodiment, monitoring device 300 is configured to generatelight at a first excitation wavelength selected to generate a firstemission response having a maximum responsive to a selected AGEprotein/lipid (e.g., HbA1c), and to generate light at a secondexcitation wavelength selected to generate a second emission responsehaving a minimum responsive to the same AGE protein/lipid (e.g., HbA1c).The respective emission responses are measured at an emission wavelengthcorresponding with the maximum (peak) of the first emission response,wherein the ratio provides an assessment of the selected AGEprotein/lipid concentration, but not relative to any other protein.

In another embodiment, monitoring device 300 is configured to generatelight at a first excitation wavelength selected to generate an emissionresponse having a maximum response to a selected AGE protein/lipid, andmeasures the emission response at a first wavelength that correspondswith a maximum (peak) of the emission response and at a secondwavelength that corresponds with a minimum of the emission response. Theratio provides an assessment of the AGE protein/lipid concentration.

In another embodiment, any of the above embodiments may be utilized inconjunction with measurements of autofluorescence lifetimes associatedwith the respective emission responses. For example, a first excitationwavelength is selected to generate a first emission response having amaximum responsive to a selected AGE protein/lipid, wherein anautofluorescence lifetime is measured with respect to the emissionresponse. A second excitation wavelength is selected to generate asecond emission response having a minimum responsive to the same AGEprotein/lipid, and an autofluorescence lifetime is measured with respectto the emission response. The ratio of the autofluorescence lifetimes isutilized to determine the concentration of AGE protein/lipid associatedwith the tissue.

FIG. 4 is a block diagram illustrating components utilized to monitoroptical signals and processing optical signals according to someembodiments.

Medical device 400 includes at least one light source 402, at least onedetector 404, filter/amplifier 406, processor/microcontroller 408,memory 410, and communication/output 412. As described above, medicaldevice 400 may be adhered to the patient's skin, clipped onto apatient's finger, attached via an arm cuff, inserted subcutaneously, orimplanted within the patient. Light source 402 emits light that isprovided incident to the patient's tissue, referred to herein as“excitation”. In some embodiments, excitation may be provided at aplurality of wavelengths or at a selected wavelength. For example, thewavelength of the emitted light may be selected based on the AGEprotein/lipid (e.g., particular protein) to be analyzed, whereindifferent wavelengths of light interact differently with particularproteins/lipids. In some embodiments, light source 402 includes aplurality of light sources each capable of emitting at a particularunique wavelength.

Light from light source 402 interacts with patient tissue 414. Theinteraction is a result of one or more processes, includingautofluorescence, absorption, and reflectance that results in theemission of light from the tissue, referred to as the emission response.The emission response is detected by the one or more photodetectors 404.In some embodiments, photodetector 404 may utilize well-known opticalsensors, such as complimentary metal-oxide-semiconductor (CMOS) sensoror a charge-coupled device (CCD) sensor. Each of the one or morephotodetectors 404 is configured to detect light at a particularemission wavelength. For embodiments in which a plurality of emissionwavelengths are monitored, a plurality of photodetectors 404 arerequired, each configured to monitor one of the desired emissionwavelengths. The emission wavelengths monitored by the one or morephotodetectors 404 are selected based on the particular AGEprotein/lipid (e.g., HbA1c) being monitored. For example, the emissionresponse morphology (i.e., amplitude of the emission response across theentire wavelength spectrum) depends on how light interacts with the AGEprotein/lipid being monitored, with emission responses for each bloodcomponent providing different emission response morphology. Inparticular, emission wavelengths monitored by the one or morephotodetectors are selected to correspond with maximum and/or minimumvalues associated with the emission response spectrum being monitored.

The one or more photodetectors convert the monitored optical signal(i.e., the emission response) to an electrical signal representative ofthe amplitude of the emission wavelength being monitored.Filter/amplifier 406 filters and amplifies the signal to provide a cleansignal to processor/microcontroller 408.

Processor/microcontroller 408 operates in conjunction with memory 410and communication output 412. In some embodiments,processor/microcontroller 408 provides the measured emission responsesignals monitored by the photodetectors to an intermediate gateway 102and/or remote monitoring center 106 (shown in FIG. 1) for subsequentprocessing. In other embodiments, processor/microcontroller 408 executesinstructions locally to perform analysis on the monitored emissionresponse. This may include calculating ratios associated with two ormore monitored emission responses, calculating blood componentconcentrations based on the calculated ratios, comparing the ratiosand/or blood component concentrations to threshold values, and/orstoring calculated ratios and/or blood component concentrations tomemory 410. Results of any analysis performed locally byprocessor/microcontroller may then be communicated to intermediatedevice 102, gateway 106, or provided as an alert to the patient (e.g.,audio alert).

FIG. 5 is a flowchart that illustrates steps utilized to measure AGEsprotein/lipid/enzyme according to embodiments of the present invention.Reference is made to FIG. 6, which is a graph illustrating relativeabsorbance (lefty-axis) of a particular AGE protein (e.g., HbA1c) atvarious wavelengths (line 602) as compared with the fluorescenceintensity (righty-axis) of upconversion nanoparticles (UNCPs) (line600), and FIG. 7, which is a graph illustrating the relationship betweenintensity of the measured emission responses as it relates to varyingconcentration levels of HbA1c. As illustrated in FIG. 6, HbA1c moleculesexhibit relatively high absorption at a wavelength of approximately 541nm (λ₁ in FIG. 6), while UNCP exhibit relatively high intensityemissions at approximately the same wavelength. Thus, as theconcentration of HbA1c molecules increases relative to the number ofUNCP particles, light absorbance increases and emitted intensitydecreases, resulting in an expected decline in intensity as HbA1cconcentration levels increase. This is confirmed in FIG. 7, whichillustrates that an increase in HbA1c concentration results in adecrease in intensity of monitored light at the mission wavelength of541 nm. These characteristics of glycated hemoglobin (HbA1c) areutilized in the embodiment described with respect to FIG. 5.

At step 502, a light source is utilized to provide excitation to patienttissue at a first excitation wavelength selected to target selected AGEmolecules (HbA1c in the example shown in FIGS. 6 and 7). For example, inone embodiment the excitation wavelength of the first light source is inthe infrared range (e.g., 700 nm to approximately 1 micron or μm),although in other embodiments other excitation wavelengths (e.g.,visible, ultra-violet spectrum) may be utilized so long as the emissionresponse provides the desired morphology. In one embodiment, theexcitation wavelength is equal to approximately 980 nm, which providesthe emission response morphology illustrated in FIG. 6, which includesthe emission response of HbA1c as well as UNCPs. In other embodiments,depending on the type of AGE molecule to be targeted, the excitationwavelength is modified to provide an emission response responsive to thetargeted AGE molecule.

At step 504, in response to the excitation signal, a first emissionresponse is generated and monitored by one or more of the photodetectorsat a first emission wavelength That is, rather than monitor the entirespectrum of wavelengths associated with the emission response, aparticular wavelength is selected for monitoring. As discussed above,monitoring the entire spectrum of wavelengths is cost-prohibitive bothin terms of the number of detectors required and processing powerrequired. The emission wavelength selected corresponds with a maximum ofthe targeted AGE molecule (e.g., HbA1c). In the embodiment shown inFIGS. 6 and 7, the first emission wavelength is equal to approximately540 nm. As illustrated in FIGS. 6 and 7, the intensity of the emissionresponse measured at this wavelength depends, at least in part, on theconcentration of targeted AGE molecules (in this case, HbA1c), but alsoon the external factors such as placement of the medical device, ambientlight, etc. To isolate the impact of the AGE molecules on the emissionresponse, a second emission response is monitored at a minimum of theemission response.

At step 506, absorption/intensity of the emission response is measuredat a second emission wavelength corresponding with a minimum of thetargeted emission response. For example, FIG. 7 illustrates that withrespect to the HbA1c molecule, local maximums exist at wavelengths ofapproximately 541 nm and 650 nm, but a minimum is provided at awavelength of approximately 600 nm. In this embodiment, the secondemission wavelength is selected at this wavelength to serve as theemission response minimum or reference. As indicated, other wavelengthsmay be selected to represent a minimum of the emission response,including wavelengths less than 500 nm, greater than approximately 675nm, and between approximately 560 nm and approximately 630 nm. Theamplitude of the emission response measured at the second wavelength(e.g., minimum of the emission response) should not vary with changes inthe concentration of the targeted AGE molecule. However, the amplitudemeasured at the second wavelength may vary based on external factorssuch as ambient light, location of the device on the patient's body,etc. Utilizing a ratio comprised of an emission response associated witha maximum and an emission response associated with a minimum orreference has the effect of canceling the external factors unrelated tothe concentration of the targeted AGE molecule.

At step 508, a ratio of the amplitude measured at the first emissionwavelength and amplitude measured at the second emission wavelength iscalculated. For example, in one embodiment the ratio is defined as themaximum emission response divided by the minimum emission response.

At step 510, the concentration of the targeted AGE molecule isdetermined based on the calculated ratio. As illustrated with respect toFIG. 7, the intensity/amplitude of HbA1c emission response decreases asthe concentration of HbA1c increases. For example, FIG. 7 illustratesemission response for HbA1c concentration levels of zero (line 700),0.025 (line 702), 0.05 (line 704), and 0.1 (line 706), with eachincrease in HbA1c concentration resulting in a decrease in the amplitudeof the emission response. As a result, the ratio (as defined above, inwhich the maximum emission response is divided by the minimum emissionresponse) decreases as the HbA1c concentration increases. In otherembodiments, the ratio may be inverted such that as the HbA1cconcentration increases, the ratio increases. The monitoredconcentration of HbA1c is utilized to monitor the risk of diabetes.

At step 512, alerts/messages are generated in response to the calculatedHbA1c level. For example, in embodiments in which the ratio calculationand calculation of the HbA1c level is done locally on the medical device100 and/or 110, an audio and/or visual alert may be provided to thepatient directly indicating the calculated HbA1c level. In addition, thecalculated HbA1c level may be communicated to a remote monitoring centerfor provision to the patient's physician. In other embodiments, theratio calculation and calculation of HbA1c levels are done remotely. Inresponse to the ratio exceeding or falling below a defined threshold, analert may be communicated to the patient's physician or may becommunicated to the patient via a messaging system.

Although in the embodiment described with respect to FIG. 5, separateexcitation wavelengths were utilized in combination with monitoring aconstant emission response wavelength, in other embodiments theexcitation wavelength may remain constant and two or more emissionwavelengths are monitored to generate the desired ratio, wherein theemission wavelengths are selected to correspond with a maximum valueassociated with the emission response and a minimum or reference valueassociated with the emission response.

FIG. 8 is a flowchart that illustrates steps utilized to measure AGEsprotein/lipid/enzyme according to an embodiment of the presentinvention. In contrast with the embodiment described with respect toFIG. 5, the embodiment shown in FIG. 8 utilizes first and secondexcitation wavelengths to excite the tissue being monitored and togenerate first and second emission responses.

At step 802, a light source is utilized to provide excitation to patienttissue at a first excitation wavelength selected to target selected AGEmolecules (e.g., HbA1c). For example, in embodiments relying onautofluorescence spectroscopy, the excitation wavelength may be selectedto correspond with the maximum autofluorescence response of the selectedAGE molecule. In the embodiment shown in FIG. 9, this maximum occurs ata wavelength of approximately 310 nm (e.g., λ₃). In other embodiments,depending on the type of AGE molecule to be targeted and the type ofspectroscopy being performed, the excitation wavelength is modified toprovide an emission response responsive to the targeted AGE molecule.

At step 804, in response to the excitation signal, a first emissionresponse is generated and monitored by one or more of the photodetectorsat a first emission wavelength λ₅. That is, rather than monitor theentire spectrum of wavelengths associated with the emission response, aparticular wavelength is selected for monitoring. As discussed above,monitoring the entire spectrum of wavelengths is cost-prohibitive bothin terms of the number of detectors required and processing powerrequired. The emission wavelength selected corresponds with a maximum ofthe emission response corresponding with the targeted AGE molecule(e.g., HbA1c). In the embodiment shown in FIG. 9, the selected emissionwavelength is equal to approximately 345 nm. When relying onautofluorescence spectroscopy, the excitation wavelength selected totarget a particular AGE protein is typically lower than thecorresponding emission wavelength, as the AGE molecules absorb energy ata lower wavelength and emit (e.g., autofluorescence) at a higherwavelength.

At step 806, a light source is utilized to provide excitation to patienttissue at a second excitation wavelength selected to minimize theemission response associated with the targeted AGE molecules (e.g.,HbA1c). In the embodiment shown in FIG. 9, the minimum corresponds witha wavelength of approximately 320 nm (λ4). That is, providing excitationat this wavelength should not result in the absorption of light by thetargeted AGE molecules and therefore should result in an emissionresponse that is minimized.

At step 808, in response to the second excitation signal provided at thesecond excitation wavelength, a second emission response is generatedand monitored by one or more of the photodetectors at a first emissionwavelength λ₅. That is, in this embodiment the emission response to thefirst and second excitation signal is monitored at the same emissionwavelength. As shown in FIG. 9, the selected emission wavelength isequal to approximately 345 nm. However, because the excitationwavelength is selected to minimize the emission response associated withthe targeted AGE molecule, high concentrations of the targeted AGEmolecule will not autofluoresce in response to the second excitationwavelength and therefore the monitored amplitude of the emissionresponse will be lower in amplitude than that measured with respect tothe first excitation wavelength.

At step 810, a ratio of the emission response measured in response tothe first excitation wavelength and the emission response measured inresponse to the second excitation wavelength is calculated. For example,in one embodiment the ratio is defined as the maximum emission responsedivided by the minimum emission response.

At step 812, the concentration of the targeted AGE molecule isdetermined based on the calculated ratio. In one embodiment, theintensity/amplitude of the first emission response increases in responseto increased AGE concentrations (e.g., increased autofluorescenceresponse). Similarly, the intensity/amplitude of the second emissionresponse remains approximately the same despite variations in thetargeted AGE concentration. As a result, in this embodiment the ratio(as defined above, in which the maximum emission response is divided bythe minimum emission response) increases as the AGE concentrationincreases. In other embodiments, the ratio may be inverted such that asthe AGE concentration increases, the ratio decreases.

At step 814, alerts/messages are generated in response to the calculatedAGE concentration level. For example, in embodiments in which the ratiocalculation and calculation of the AGE concentration level is donelocally on the medical device 100 and/or 110, an audio and/or visualalert may be provided to the patient directly indicating the calculatedAGE concentration level. In addition, the calculated AGE concentrationlevel may be communicated to a remote monitoring center for provision tothe patient's physician. In other embodiments, the ratio calculation andcalculation of AGE concentration levels are done remotely. In responseto the ratio exceeding a defined threshold, an alert may communicated tothe patient's physician or may be communicated to the patient via amessaging system.

FIG. 10 is a flowchart that illustrates steps utilized to measure AGEsprotein/lipid/enzyme according to another embodiment of the presentinvention. In contrast with the embodiment described with respect toFIGS. 5 and 8, the embodiment shown in FIG. 10 utilizes first and secondexcitation wavelengths to excite the tissue being monitored and togenerate first and second emission responses. Fluorescent decay of theemission responses are monitored as shown in FIG. 11, and ratios arecalculated based on the monitored decay (e.g., time length of decay,average monitored value over defined time period, etc.).

At step 1002, a light source is utilized to provide excitation topatient tissue at a first excitation wavelength selected to targetselected AGE molecules (e.g., HbA1c). For embodiments in whichfluorescence decay is being monitored, the excitation wavelength isselected to be absorbed by the targeted AGE molecule such that anautofluorescence emission is generated. In the embodiment described withrespect to FIGS. 8 and 9, a wavelength of approximately 310 nm wasselected as an excitation maximum for glycated hemoglobin (HbA1c). Inother embodiments, depending on the type of AGE molecule to be targetedand the type of spectroscopy being performed, the excitation wavelengthis modified to provide an emission response responsive to the targetedAGE molecule.

At step 1004, in response to the excitation signal, a first emissionresponse is generated and fluorescent decay of the emission signal ismonitored by one or more of the photodetectors at a first emissionwavelength. For example, FIG. 11 illustrates the fluorescent decay 1100of the first emission response over time t. Rather than measure anamplitude/intensity of the emission response at a particular emissionwavelength (as described with respect to FIGS. 5-9), in this embodimentthe fluorescent decay of the emission response is measured as shown inFIG. 11, in which the amplitude/intensity of the emission response 1100increases to a maximum in response to the excitation signal and thendecays over time t to a steady state value. The emission wavelengthselected to measure the fluorescent decay corresponds with a significant(e.g., maximum) associated with the emission response of the selectedAGE molecule. In the embodiment shown in FIG. 9, the selected emissionwavelength is equal to approximately 345 nm. When relying onautofluorescence spectroscopy, the excitation wavelength selected totarget a particular AGE protein is typically lower than thecorresponding emission wavelength, as the AGE molecules absorb energy ata lower wavelength and emit (e.g., autofluorescence) at a higherwavelength.

In one embodiment, autofluorescence decay is a measure of the time t ittakes for the autofluorescence response to decay to a defined percentageof the maximum or peak. The measured decay is representative of theconcentration of selected AGE molecules, with increased decay timesindicating an increase in concentration of AGE molecules. In otherembodiments, rather than measure a length of time between a determinedpeak and a decay threshold, the fluorescent decay is quantized byaveraging the amplitude/intensity over a period of time and/orintegrating the fluorescent decay to generate a value representative ofthe decay rate.

At step 1006, a light source is utilized to provide excitation topatient tissue at a second excitation wavelength. In one embodiment, thesecond excitation wavelength is selected to provide a reference emissionresponse associated with the targeted AGE molecules (e.g., HbA1c). Forexample, as described with respect to FIG. 9 above, the excitationwavelength corresponding with the excitation minimum is equal toapproximately 320 nm. That is, providing excitation at this wavelengthshould not result in the absorption of light by the targeted AGEmolecules and therefore should result in an emission response that isminimized, thereby providing a reference emission response to becompared with the first emission response.

In other embodiments, rather than select the second excitationwavelength to correspond with a minimum absorption wavelength of the AGEmolecule targeted by the first excitation wavelength, the secondexcitation wavelength may be selected to correspond with a maximumresponse of a different molecule (e.g., hemoglobin (Hb)). In thisembodiment, the ratio defines the relationship between the concentrationof the first targeted AGE molecule and the second targeted molecule(e.g., Hb).

At step 1008, in response to the second excitation signal provided atthe second excitation wavelength, a second emission response isgenerated and fluorescent decay is monitored by one or more of thephotodetectors at a first emission wavelength. For example, FIG. 11illustrates the fluorescent decay 1102 of the first emission responseover time t. That is, in this embodiment the emission response to thefirst and second excitation signal is monitored at the same emissionwavelength. As shown in FIG. 9, the selected emission wavelength isequal to approximately 345 nm. However, because the excitationwavelength is selected to minimize the emission response associated withthe targeted AGE molecule, high concentrations of the targeted AGEmolecule will not autofluorescence in response to the second excitationwavelength and therefore the monitored fluorescent decay of the emissionresponse will be shorter than that measured with respect to the firstexcitation wavelength. As discussed above, in some embodiments thefluorescent decay is monitored for a period of time and an averageand/or integral that quantifies the fluorescence decay is calculated.

In other embodiments, in which the second excitation wavelength isselected to correspond with a different molecule, then at step 1008 asecond emission wavelength may be selected that corresponds with theemission response of the different molecule (e.g. Hb) and thefluorescent decay may be measured with respect to the emission responseat the second wavelength. Similarly, other methods of quantifying thefluorescent decay may be relied upon as discussed above. As describedabove, if the second excitation wavelength is selected to correspondwith a different molecule, then the ratio calculated at step 1010represents the relationship between the concentration of the first AGEmolecule and the second targeted molecule (e.g., Hb).

At step 1010, a ratio of the fluorescent decays measured in response tothe first excitation wavelength and the emission response measured inresponse to the second excitation wavelength is calculated. As discussedabove, if the excitation wavelengths are selected to correspond with amaximum emission response and a minimum emission response of a selectedAGE protein/lipid, then the ratio represents the concentration of theselected AGE protein/lipid. If the first and second excitationwavelengths are selected to correspond with different molecules (e.g.,HbA1c and Hb, respectively) then the ratio calculated at step 1010 isrepresentative of the relationship between concentration levels of theselected molecules. Depending on the application, one ratio may havebenefits over the other.

At step 1012, the concentration of the targeted AGE molecule isdetermined based on the calculated ratio. In one embodiment, theautofluorescent decay of the first emission response increases inresponse to increased AGE concentrations (e.g., increasedautofluorescence response). Similarly, the autofluorescent decay of thesecond emission response remains approximately the same despitevariations in the targeted AGE concentration. As a result, in thisembodiment the ratio (as defined above, in which the maximum emissionresponse is divided by the minimum emission response) increases as theAGE concentration increases. In other embodiments, the ratio may beinverted such that as the AGE concentration increases, the ratiodecreases.

In embodiments in which first and second excitation wavelengths areselected to target first and second molecules, then the ratio calculatedat step 1012 represents the concentration of the targeted AGE moleculerelative to concentration of a different molecule (e.g. Hb). In someembodiments, in which a molecule such as hemoglobin is converted to anAGE molecule (e.g., HbA1c) then this relationship can be a useful metricin monitoring progression of a disease of efficacy of therapy.

At step 1014, alerts/messages are generated in response to thecalculated AGE concentration level. For example, in embodiments in whichthe ratio calculation and calculation of the AGE concentration level isdone locally on the medical device 100 and/or 110, an audio and/orvisual alert may be provided to the patient directly indicating thecalculated AGE concentration level. In addition, the calculated AGEconcentration level may be communicated to a remote monitoring centerfor provision to the patient's physician. In other embodiments, theratio calculation and calculation of AGE concentration levels are doneremotely. In response to the ratio exceeding a defined threshold, analert may communicated to the patient's physician or may be communicatedto the patient via a messaging system.

In this way, FIGS. 5-11 illustrate various ways in which AGEconcentration levels in patient tissue and/or blood may be monitored. Inone embodiment (shown in FIGS. 5-7), a single excitation source isutilized in combination with at least two detectors. The emissionwavelengths monitored by the at least two detectors correspond with amaximum of the emission response of the targeted AGE molecule and asignificant minimum. In another embodiments (shown in FIGS. 8 and 9), apair of excitation sources are utilized in combination with at least onedetector. The first and second excitation sources emit light at firstand second excitation wavelengths selected to generate an emissionresponse targeting the AGE molecule to be monitored. This may includeselecting an excitation wavelength that corresponds with a maximumemission response (e.g., maximum absorption, autofluorescence, etc.) ofthe AGE molecule to be monitored in combination with a minimum emissionresponse (e.g., minimum absorption, autofluorescence, etc.) of the sameAGE molecule. In other embodiments, the first excitation wavelength maybe selected to correspond with a maximum emission response of a firstAGE molecule and the second excitation wavelength may be selected tocorrespond with a maximum emission response of a second molecule (e.g.,Hb). In another embodiment (shown in FIGS. 10 and 11), utilizing eithercombination of excitation sources and photodetectors described above,autofluorescence decay is monitored in lieu of amplitude/intensity ofthe emission response. The autofluorescence decay may be measured interms of time required for the emission response to delay from a peakvalue to a threshold decay value, rate of change (slope) or may bequantified as an average value and/or integral of the fluorescencedecay. Depending on the combination of excitation sources and emissiondetectors, at least a first autofluorescence decay is measured and asecond autofluorescence decay is measured, wherein the ratio is utilizedto determine concentration of an AGE molecule.

FIG. 12 is a flowchart that illustrates long-term (e.g., chronic)monitoring and storage of a particular species of AGE, (e.g.glycosylated hemoglobin A1c (HbA1c)).

At step 1202, one or more initial ratio(s) are measured based on one ormore excitation wavelengths and one or more emission wavelengths. Forexample, as discussed with respect to FIG. 5, an excitation wavelengthsare utilized to generate an emission response that is monitored withrespect to a first emission wavelength and a second emission wavelength.In this embodiment, a light source is utilized along with at least twophotodetectors, but in other embodiments a two or more light sources maybe utilized in conjunction with a single photodetector.

At step 1204, the HbA1c concentration is calculated based on the initialratio(s) and is stored as a personalized/baseline HbA1c value associatedwith the patient. Determining a personalized/baseline HbA1c value may beuseful in long-term monitoring of the patient. For example, long-termmonitoring of HbA1c values from a baseline value may be useful inassessing patient compliance with diabetes medication, monitoring theprogression of diseases such as diabetes, and/or monitoring thestability of the disease.

At step 1206, the personalized/baseline HbA1c value is utilized to setalarm/warning thresholds. Alarm/warning thresholds may be set based onboth the personalized/baseline HbA1c value as well as based on fixedHbA1c levels. For example, in some embodiments the monitored HbA1cvalues are compared to fixed threshold values to determine whether thepatient's glycosylated hemoglobin levels have exceeded or fallen belowthe threshold value. In other embodiments, for example with respect tomonitoring disease stability and/or progression, the monitored HbA1cvalues are compared to the initial or personalized HbA1c value. In someembodiments, the alarm/warning thresholds are set to notify the patientand/or medical personnel in response to progression of diseases such asdiabetes based on the monitored HbA1c values. As the disease progresses,the HbA1c concentration level increases. In this way, the alarm/warningthresholds can be utilized to monitor patient compliance with diabetesmedication, disease stability, and/or disease progression.

At step 1208, one or more ratios are monitored, utilized to calculate anHbA1c concentration level, and compared to the alarm/warning thresholdsto detect patient conditions. For example, if the measured HbA1cconcentration level increases, this is an indication that the patient isnot taking the prescribed medication, or that the disease is progressingand requires additional therapeutic interventions.

At step 1210, an alert is generated in response to the monitored ratioexceeding or falling below one or more of the thresholds. In someembodiments, when a threshold is crossed, this triggers additionalmeasurements in order to confirm the accuracy of the result. This mayinclude increasing the frequency at which readings are taken, or simplycontinuing to monitor to ensure that the measured ratios are accurate.

The alert may be provided to the patient in the form of an audio orvisual alert. The alert may also be communicated to the intermediategateway 102 or remote monitoring center 106 (shown in FIG. 1). The alertmay be provided to a physician or expert for analysis and confirmationof the detected patient condition.

One of the benefits of the embodiment described with respect to FIG. 12,in combination with adherent and/or insertable devices is that theyallow for long-term monitoring of trends in HbA1c concentration levels.In particular, the utilization of ratios minimizes the effect ofexternal influences and noise (such as changing ambient lightconditions, etc.), and initialization of the ratio to an average valuemonitored over an initial monitoring period allows the ratios to bepersonalized for each patient (to account for differences in thephysiology of each patient).

Although the embodiment described with respect to FIG. 12 was specificto HbA1c monitoring as it relates to diabetes detection and pre-diabetesdetection, in other embodiments various other AGE molecules may bemonitored, both in the patient's bloodstream and/or in patient tissue.For example, evidence of AGE concentration levels in various tissue suchas cardiac tissue, dermal tissue, or others may be monitored to detectrisk conditions and/or monitor chronic conditions.

While the invention has been described with reference to an exemplaryembodiment(s), it will be understood by those skilled in the art thatvarious changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings of the invention without departing from theessential scope thereof. Therefore, it is intended that the inventionnot be limited to the particular embodiment(s) disclosed, but that theinvention will include all embodiments falling within the scope of theappended claims.

1. A method comprising: providing incident light to tissue of a patient at an excitation wavelength; monitoring an emission response to the incident light at a first emission wavelength and at a second emission wavelength; and determining a concentration of an advanced glycation end-product (AGE) based on a ratio of the emission response at the first emission wavelength to the emission response at the second emission wavelength.
 2. The method of claim 1, wherein the emission response at the first emission wavelength is associated with a maximum of the emission response and the emission response at the second emission wavelength is associated with a minimum of the emission response.
 3. The method of claim 1, wherein the AGE is glycated hemoglobin (HbA1c).
 4. The method of claim 3, further comprising determining a risk of diabetes based on the determined concentration of HbA1c.
 5. The method of claim 1, wherein monitoring the emission response comprises monitoring an autofluorescence decay of the emission response at the first emission wavelength and the emission response at the second emission wavelength.
 6. The method of claim 5, wherein monitoring the autofluorescence decay comprises measuring a first rate of decay of the emission response at the first emission wavelength and a second rate of decay of the emission response at the second emission wavelength, and wherein determining the concentration of the AGE comprises calculating the concentration of the AGE based on a ratio of the first rate of decay to the second rate of decay.
 7. The method of claim 1, further comprising: comparing the determined concentration to threshold; and generating an alert based on the comparison.
 8. The method of claim 1, wherein monitoring the emission response comprising monitoring a first amplitude at the first emission wavelength and a second amplitude at the second emission wavelength.
 9. The method of claim 1, wherein providing the incident light and monitoring the emission response comprises providing the incident light and monitoring the emission response with a medical device implanted in the patient.
 10. The method of claim 1, wherein providing the incident light and monitoring the emission response comprises providing the incident light and monitoring the emission response with a medical device subcutaneously inserted in the patient.
 11. A system comprising: a medical device comprising: a light emitter configured to provide incident light to tissue of a patient at an excitation wavelength; and at least one photodetector configured to monitor an emission response to the incident light at a first emission wavelength and at a second emission wavelength; and one or more processors configured to determine a concentration of an advanced glycation end-product (AGE) based on a ratio of the emission response at the first emission wavelength to the emission response at the second emission wavelength.
 12. The system of claim 11, wherein the emission response at the first emission wavelength is associated with a maximum of the emission response and the emission response at the second emission wavelength is associated with a minimum of the emission response.
 13. The system of claim 11, wherein the AGE is glycated hemoglobin (HbA1c).
 14. The system of claim 13, wherein the one or more processors are configured to determine a risk of diabetes based on the determined concentration of HbA1c.
 15. The system of claim 11, wherein the at least one photodetector is configured to monitor an autofluorescence decay of the emission response at the first emission wavelength and the emission response at the second emission wavelength.
 16. The system of claim 15, wherein the at least one photodetector is configured to measure a first rate of decay of the emission response at the first emission wavelength and a second rate of decay of the emission response at the second emission wavelength, and the one or more processors are configured to determine the concentration of the AGE based on a ratio of the first rate of decay to the second rate of decay.
 17. The system of claim 11, wherein the one or more processors are configured to: compare the determined concentration to threshold; and generate an alert based on the comparison.
 18. The system of claim 11, wherein the at least one photodetector is configured to monitor a first amplitude at the first emission wavelength and a second amplitude at the second emission wavelength.
 19. The system of claim 11, wherein the one or more processors comprises a processor of the medical device.
 20. The system of claim 11, wherein the medical device is configured for implantation in the patient. 